ANCA-Associated Vasculitis: Core Curriculum 2020 Duvuru Geetha, J. Ashley Jefferson  American Journal of Kidney Diseases  DOI: 10.1053/j.ajkd.2019.04.031 Copyright © 2019 National Kidney Foundation, Inc. Terms and Conditions

Figure 1 Pathogenesis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. ANCA autoantigens (proteinase 3 [PR3] and myeloperoxidase [MPO]) are normally sequestered in the primary granules of neutrophils. Infection or other environmental stimuli result in neutrophil priming, with movement of PR3 and MPO to the cell surface. Binding of ANCA to these autoantigens results in activation of neutrophils, which adhere to vascular endothelium. Neutrophil degranulation leads to the release of reactive oxygen species (ROS), proteases, and neutrophil extracellular traps (NETs), damaging the endothelium. Chemokines and tissue deposition of PR3 and MPO result in the recruitment of autoreactive T cells and monocytes augmenting tissue injury. Drawings created with BioRender. American Journal of Kidney Diseases DOI: (10.1053/j.ajkd.2019.04.031) Copyright © 2019 National Kidney Foundation, Inc. Terms and Conditions

Figure 2 Role of complement in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. ANCA binding to autoantigens (proteinase 3 and myeloperoxidase) on the cell surface results in neutrophil activation and release of factors (properdin) that activate the alternate pathway of complement. The membrane attack complex (MAC; C5b-9) plays a limited role, but generation of the anaphylatoxin C5a attracts further neutrophils, and on binding to the cell surface C5a receptor (CD88) enhances neutrophil priming and activation, resulting in the formation of an amplification loop promoting inflammation. Neutrophil drawing created with BioRender. American Journal of Kidney Diseases DOI: (10.1053/j.ajkd.2019.04.031) Copyright © 2019 National Kidney Foundation, Inc. Terms and Conditions

Figure 3 Kidney pathology. Light microscopy images (Jones methenamine silver stain) show typical features of a necrotizing crescentic glomerulonephritis: (A) glomerulus with segmental necrosis (arrow) and (B) large glomerular crescent (arrow) filling most of Bowman space and compressing the glomerular tuft. Less commonly seen is (C) necrotizing extraglomerular vasculitis (arrow), and rarely, (D) medullary angiitis (arrow) with prominent neutrophils. Images provided courtesy of Shreeram Akilesh. American Journal of Kidney Diseases DOI: (10.1053/j.ajkd.2019.04.031) Copyright © 2019 National Kidney Foundation, Inc. Terms and Conditions

Figure 4 (A, B) Proposed treatment algorithm for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. αMaintenance therapy should be individualized according to the risk for relapse. Patients with myeloperoxidase (MPO)-ANCA have a lower relapse risk and a shorter duration (18-24 months) of therapy may be appropriate after initial presentation. βData are limited in patients with advanced kidney failure at presentation; the authors prefer a cyclophosphamide (CYC)-based regimen, such as that used in the RITUXVAS trial in this setting. γPatients who have reached end-stage kidney disease and have no extrarenal manifestations may not require maintenance immunosuppression. Abbreviations: AZA, azathioprine; GC, glucocorticoids; MMF, mycophenolate mofetil; PR3, proteinase 3; RTX, rituximab. American Journal of Kidney Diseases DOI: (10.1053/j.ajkd.2019.04.031) Copyright © 2019 National Kidney Foundation, Inc. Terms and Conditions